The S1P mimetic fingolimod phosphate regulates mitochondrial oxidative stress in neuronal cells

Free Radic Biol Med. 2019 Jun;137:116-130. doi: 10.1016/j.freeradbiomed.2019.04.022. Epub 2019 Apr 26.

Abstract

Fingolimod is one of the few oral drugs available for the treatment of multiple sclerosis (MS), a chronic, inflammatory, demyelinating and neurodegenerative disease. The mechanism of action proposed for this drug is based in the phosphorylation of the molecule to produce its active metabolite fingolimod phosphate (FP) which, in turns, through its interaction with S1P receptors, triggers the functional sequestration of T lymphocytes in lymphoid nodes. On the other hand, part if not most of the damage produced in MS and other neurological disorders seem to be mediated by reactive oxygen species (ROS), and mitochondria is one of the main sources of ROS. In the present work, we have evaluated the anti-oxidant profile of FP in a model of mitochondrial oxidative damage induced by menadione (Vitk3) on neuronal cultures. We provide evidence that incubation of neuronal cells with FP alleviates the Vitk3-induced toxicity, due to a decrease in mitochondrial ROS production. It also decreases regulated cell death triggered by imbalance in oxidative stress (restore values of advanced oxidation protein products and total thiol levels). Also restores mitochondrial function (cytochrome c oxidase activity, mitochondrial membrane potential and oxygen consumption rate) and morphology. Furthermore, increases the expression and activity of protective factors (increases Nrf2, HO1 and Trx2 expression and GST and NQO1 activity), being some of these effects modulated by its interaction with the S1P receptor. FP seems to increase mitochondrial stability and restore mitochondrial dynamics under conditions of oxidative stress, making this drug a potential candidate for the treatment of neurodegenerative diseases other than MS.

Keywords: Antioxidant; Fingolimod; Fingolimod phosphate; Mitochondria; Neuroprotection; Oxidative stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / pharmacology*
  • Cell Death
  • Cell Line
  • Dopaminergic Neurons / metabolism*
  • Dopaminergic Neurons / pathology
  • Fingolimod Hydrochloride / chemistry
  • Fingolimod Hydrochloride / pharmacology*
  • Fingolimod Hydrochloride / therapeutic use
  • Humans
  • Lysophospholipids / metabolism
  • Membrane Potential, Mitochondrial
  • Mice
  • Mitochondria / metabolism*
  • Molecular Mimicry
  • Multiple Sclerosis / drug therapy*
  • Neuroprotection
  • Oxidative Stress / drug effects
  • Oxygen Consumption
  • Phosphates / chemistry
  • Reactive Oxygen Species / metabolism
  • Sphingosine / analogs & derivatives
  • Sphingosine / metabolism
  • Sphingosine-1-Phosphate Receptors / metabolism*
  • Vitamin K 3 / toxicity

Substances

  • Antioxidants
  • Lysophospholipids
  • Phosphates
  • Reactive Oxygen Species
  • Sphingosine-1-Phosphate Receptors
  • sphingosine 1-phosphate
  • Vitamin K 3
  • Fingolimod Hydrochloride
  • Sphingosine